Description

• Title:
  Membrane cholesterol content plays a key role in the neurotoxicity of b-amyloid: implications for Alzheimer’s disease
• Creator:
  Abramov, Andrey Y.;
  Ionov, Maksim;
  Pavlov, Evgeny;
  Duchen, Michael R.
• Contributor:
  Andrey Y. Abramov - Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;
  Maksim Ionov - Department of General Biophysics, University of Lodz, Banacha st. 12 ⁄ 16, Lodz 90-237, Poland;
  Evgeny Pavlov - Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada;
  Michael R. Duchen - Department of Cell and Developmental Biology and Consortium for Mitochondrial research, University College London, London WC1E 6BT, UK
• Description:
  Beta amyloid (βA) plays a central role in the pathogenesis of the most common and devastating neurodegenerative disorder, Alzheimer's disease (AD). The mechanisms of βA neurotoxicity remain controversial, but include dysregulation of calcium homeostasis and oxidative stress. A large body of data suggest that cholesterol plays a significant role in AD. In mixed cultures containing hippocampal neurons and astrocytes, we have shown that neurotoxic βA peptides (1-42 and 25-35) cause sporadic cytosolic calcium ([Ca(2+) ](c) ) signals in astrocytes but not in neurons, initiating a cascade that ends in neuronal death. We now show, using the cholesterol-sensitive fluorescent probe, Filipin, that membrane cholesterol is significantly higher in astrocytes than in neurons and mediates the selective response of astrocytes to βA. Thus, lowering [cholesterol] using mevastatin, methyl-β-cyclodextrin or filipin prevented the βA-induced [Ca(2+) ](c) signals, while increased membrane [cholesterol] increased βA-induced [Ca(2+) ](c) signals in both neurons and astrocytes. Addition of βA to lipid bilayers caused the appearance of a conductance that was significantly higher in membranes containing cholesterol. Increasing membrane [cholesterol] significantly increased βA-induced neuronal and astrocytic death. We conclude that a high membrane [cholesterol] promotes βA incorporation into membranes and increased [Ca(2+) ](c) leading to cell death.;
  This work was supported by Clinical Research and Development Committee grant. We thank Dr. French (University of Calgary) for use of the bilayer set-up.
• Object availability:
  free access
• Date:
  2014.06.10;
  2011.04.11
• Type:
  Article
• Language:
  English
• Format:
  application/pdf
• Publisher:
  Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland
• Relation:
  Aging Cell;Volume 10, Issue 4
• Subject:
  astrocyte;
  calcium;
  cholesterol;
  neurodegeneration;
  neuron;
  β-amyloid
• Identifier:
  Abramov, A. Y., Ionov, M., Pavlov, E. and Duchen, M. R. (2011), Membrane cholesterol content plays a key role in the neurotoxicity of β-amyloid: implications for Alzheimer’s disease. Aging Cell, 10: 595–603. doi: 10.1111/j.1474-9726.2011.00685.x;
  1474-9726;
  doi: 10.1111/j.1474-9726.2011.00685.x ;http://hdl.handle.net/11089/4964
• Data provider:
  Repozytorium Uniwersytetu Łódzkiego
• Can I use it?:
  seek permission
• Type:
  image